Bone loss is among the most disabling and costly conditions suffered by Americans, and can be caused by traumatic injury, inflammatory and infectious diseases, congenital defects or oncologic resection. Conventional treatment involves harvesting bone grafts from the patient or another tissue donor for repair of the defect. These approaches face limitations such as donor site morbidity, insufficient or poor quality donor tissue, and potential immunogenicity. Stem cell-based therapy offers a promising alternative approach for the repair of bone loss such as cranial and long bone defects, however, treating large bony defects remains one major challenge. A critical barrier to progress in the field is the lack of suitable cell carriers that can support stem cell survival, and guide vascularized and mineralized bone formation in situ. To address the above challenges, our proposed multidisciplinary approach aims to validate the efficacy of microribbon-based scaffolds as a novel type of cell carrier for enhancing stem cell survival and mineralized bone matrix deposition in vivo. The proposed work will be accomplished by an interdisciplinary research team comprised of basic and clinician scientists, with complementary expertise in biomaterials, stem cells, molecular imaging and animal models to validate the efficacy of novel tissue engineering strategies for bone repair. We have demonstrated the unique microribbon morphology confers markedly enhanced mechanical strength of the scaffolds, with interconnected macroporosity to support cell proliferation and extracellular matrix formation. We hypothesize that: (1) osteogenic differentiation of adipose-derived stem cells (ADSCs) in microribbon-based scaffolds can be enhanced by tuning the stiffness and biochemical cues of microribbons; and (2) the macroporosity of microribbon-based scaffolds would lead to enhanced cell survival, faster vascularization and enhanced bone tissue formation in vivo. To test these hypotheses, three specific aims will be pursued including (1) Develop and characterize poly(ethylene glycol) (PEG)-based microribbons for forming 3D macroporous cell niche with independently tunable biochemical and mechanical cues; (2) Determine the optimal biochemical ligands and stiffness of PEG-based microribbons that support osteogenic differentiation of human adipose-derived stromal cells in vitro; and (3) Assess the efficacy of microribbon-based scaffolds for repairing bony defects in vivo using a murine cranial defect model. We expect the findings from this proposal would improve the current treatment options for bone loss, a debilitating condition that afflicts individuals across all populations and ages, and correspondingly reduce the associated socio-economical burden on society.